Rio Ferdinand and Jonny Evans are both unavailable for the Manchester derby at Old Trafford, having suffered calf and ankle injuries respectively in the past week.
Ferdinand has not recovered from the problem he sustained in the warm-up ahead of Manchester United's shock defeat at Wolves last week, while Evans played in that game but missed Northern Ireland's hammering by Scotland on Wednesday and is still sidelined.
"Rio Ferdinand got a calf injury last week. He will be out for a couple of weeks,'' Ferguson said. "Jonny Evans was injured in training with Northern Ireland. He is out so Chris Smalling will play. I am sure he will do well.''
Smalling, 21, signed for United from Fulham last January - staying at the Cottagers on loan before moving to Old Trafford on a full-time basis last summer.
He has made ten starts for the Red Devils this season, with four of them coming in the Champions League, though the Manchester derby represents the most high-profile game the England Under-21 defender has been involved in for United.
The game comes a week after United surrendered their unbeaten run with a defeat at Wolves, but Ferguson says the loss will not affect his side.
"This unbeaten run was always hanging over us," Ferguson said. "The focus has changed from that to winning the league again. That is the name of the game. In normal circumstances, and it has proved itself again, you do lose games in the Premier League.
"In the run-in to the end of the season, teams will drop points. It is a fact. Whoever gets the most consistent form will win the league."
Meanwhile, Ferguson refused to be drawn on comments made by Giovanni Trapattoni on Wednesday that Darron Gibson needs to seek a move away from Old Trafford in order to play more regular first-team football.
"I don't know in what context he said it,'' Ferguson said. "The media today can exaggerate anything now. It may have been a simple message for Darron. Who knows?
"I only picked up the headline of it yesterday and didn't really bother about the content. I know Trapattoni. He is a sensible, experienced man. I don't really give much credence to it. I don't think he would say it to cause mischief.''
Meanwhile, United are in talks with Belgian giants Anderlecht over their talented youngster Adnan Januzaj. The left-footed attacking midfielder, who has just turned 16, has attracted interest from many European clubs, including Aston Villa and French League 1 leaders Lille. Anderlecht, Januzaj's club since the age of ten, have confirmed the negotiations, saying United's interest is a compliment for their youth academy. Both clubs are now talking about how to finalise the transfer in the best possible way.